Imiquimod, 4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) is an immune response modifier, useful for treating viral infections such as genital warts. Imiquimod is disclosed in U.S. Pat. Nos. 4,689,338 and 5,238,944 and has the structure (VIII).

Several methods are known in the prior art for making Imiquimod (VIII).
The process of converting 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline (II) to 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) has been disclosed in WO 2004/0011462 A1, WO 2004/009593 A1 using peracetic acid in toluene as a solvent. This conversion is also reported in WO 92/15581, WO 9206093 and U.S. Pat. No. 5,175,296 using a combination of formic acid and peracetic acid. However, since the yields are poor and reaction being incomplete there is a need to develop an oxidation process with milder conditions.
Reported prior arts describe various methods for the preparation of 4-Amino-1-isobutyl-1H-imidazo[4,5-c]quinoline (VIII) i.e. Imiquimod wherein the Introduction of amino function in the 4-position is described in three ways. Nucleophilic substitution of a leaving group e.g. Cl or triflate with ammonia, dibenzylamine or an azido group is the first method. The second, is by reacting 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with ammonium hydroxide or its salts in presence of tosylchloride at 0-5° C. The third reported method is by reacting 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide with benzoyl isocyanate.
Patents WO 2004/009593, WO 92/06093 and U.S. Pat. Nos. 5,395,937; 5,756,747; 4,988,815; 5,602,256; 5,578,727; 4,698,348; 4,689,388 as well as European patents EP 145340, EP 0385630, EP 310950 and JP 04193866 and examples therein, describe nucleophilic substitution reactions.
In WO 97/48704 the amino group is introduced by reaction of a 4-Chloro derivative with Sodium azide to obtain a tetrazole moiety. Treatment of the tetrazole moiety with triphenyl phosphine gives the 4-amino derivative.
In U.S. Pat. No. 5,395,937 a 4-triflate derivative reacts with dibenzylamine to give 4-dibenzylamino derivative. Subsequent catalytic reduction gives the desired amino function in 4-position.
U.S. Pat. No. 5,756,747 discloses the nucleophilic substitution with ammonia on the corresponding 4-chloro derivative, which is prepared by isomerization of 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) via the 4-hydroxy derivative followed by reaction with POCl3. Several patents disclose nucleophilic substitution of 4-Chloro-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (V) with ammonia at high temperature and high pressure. These include U.S. Pat. No. 4,988,815; U.S. Pat. No. 5,602,256; U.S. Pat. No. 5,578,727; U.S. Pat. No. 4,698,348; U.S. Pat. No. 4,689,388; EP 145340; EP 0385630; EP 310950 and JP 04193866.
The patents WO 2004/009593, US2004138459, disclose a process for the preparation of 4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) (i.e. Imiquimod) by introducing an amino group in the 4-position via 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-4-phthalimide intermediate (i.e. phthalimido protecting group).
WO 92/06093 discloses reaction of 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with ammonium hydroxide or ammonium salts in the presence of tosyl chloride at 0 to 5° C. to give Imiquimod.
WO 92/15581 relates to reaction of 1-Isobutyl-1H-imidazo-[4,5-c]-quinoline-5-N-oxide (III) with benzoyl isocyanate which on subsequent hydrolysis yields Imiquimod (VIII).
Purification of Imiquimod has been described via formation of pharmaceutical salts in WO 2004/009593, U.S. Pat. No. 4,689,338 i.e. using HCl, H2SO4, H3PO4, HNO3 and Methane sulfonic acid. There is still a need for preparation of 4-Amino-1-isobutyl-1H-imidazo-[4,5-c]-quinoline (VIII) namely Imiquimod in high yield and purity.